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The effects of tree shelters on the survival, height and diameter growth of three coniferous tree species – Scots pine (Pinus sylvestris L.), Norway spruce (Picea abies (L.) H. Karst.) and Silver fir (Abies alba Mill.) were observed. The study was conducted in two experimental plantations, established in the spring of 2016 in the Training and Experimental Forest Range Jundola (Central South Bulgaria). Three experimental variants with tree shelters – Tubex Ventex Classic, Layflat Shelterguard, Layflat Treeguard and a control one (without tree shelters) were used. Twenty to twenty-five seedlings in three replications of each variant and tree species were planted. The experimental plantation 1 included Scots pine and Norway spruce and was established on a south east-facing terrain at an altitude of 1400 m. The soil is Cambisols (FAO) mixture of clay and sandy, medium stony, medium deep to deep. The habitat is medium rich, slightly moist. The experimental plantation 2 is of Silver fir and was located on an east-facing terrain at an altitude of 1400 m. The soil is Cambisols (FAO) mixture of clay and sandy, medium stony, medium deep to deep. The habitat is medium rich, slightly moist to moist. In the autumn of the fifth year after the establishment, inventories and measurements of heights, height increment and groundline diameter of the seedlings were made. The survival in both experimental plantations was higher in the variants with tree shelter. The height growth of all tree species was better in tree shelter variants, with the highest average height in the variant with Tubex Ventex Classic. The biggest height increment was established in the variant with Layflat Shelterguard for Norway spruce and Silver fir and in variant without tree shelters for Scots pine. The ground line diameter was highest in control variant for Scots pine and Norway spruce and in the variant with Layflat Treegard for the Silver fir.

The effects of tree shelters on the survival, height and diameter growth of three coniferous tree species – Scots pine (Pinus sylvestris L.), Norway spruce (Picea abies (L.) H. Karst.) and Silver fir (Abies alba Mill.) were observed. The study was conducted in two experimental plantations, established in the spring of 2016 in the Training and Experimental Forest Range Jundola (Central South Bulgaria). Three experimental variants with tree shelters – Tubex Ventex Classic, Layflat Shelterguard, Layflat Treeguard and a control one (without tree shelters) were used. Twenty to twenty-five seedlings in three replications of each variant and tree species were planted. The experimental plantation 1 included Scots pine and Norway spruce and was established on a south east-facing terrain at an altitude of 1400m. The soil is Cambisols (FAO) mixture of clay and sandy, medium stony, medium deep to deep. The habitat is medium rich, slightly moist. The experimental plantation 2 is of Silver fir and was located on an east-facing terrain at an altitude of 1400m. The soil is Cambisols (FAO) mixture of clay and sandy, medium stony, medium deep to deep. The habitat is medium rich, slightly moist to moist. In the autumn of the fifth year after the establishment, inventories and measurements of heights, height increment and groundline diameter of the seedlings were made. The survival in both experimental plantations was higher in the variants with tree shelter. The height growth of all tree species was better in tree shelter variants, with the highest average height in the variant with Tubex Ventex Classic. The biggest height increment was established in the variant with Layflat Shelterguard for Norway spruce and Silver fir and in variant without tree shelters for Scots pine. The ground line diameter was highest in control variant for Scots pine and Norway spruce and in the variant with Layflat Treegard for the Silver fir.

The effects of tree shelters on the survival, height, and diameter growth of three deciduous tree species – common beech (Fagus sylvatica L.), sycamore (Acer pseudoplatanus L.) and sessile oak (Quercus petraea Matt. (Liebl.) were studied. The study was conducted in two experimental plantations, established in the spring of 2018 in the Training and Experimental Forest Range Petrohan (North-Western Bulgaria). Four experimental variants with tree shelters – Tubex Ventex Classic, Tubex Ventex Clear, Layflat Shelterguard, Layflat Treeguard and a control one (without tree shelters) were used. Twenty to twenty-seven seedlings in three replications of each variant and tree species were planted. The experimental plantation-1 was established on an east-facing flat terrain at an altitude of 600 m. The soil is Grey Luvisol mixture of sandy and clay, slightly stony, and very deep. The site class is medium rich to rich. The experimental plantation-2 is located in a high-density game area. The area is a meadow, aspect north, slope with gradient 8o and an altitude of 850 m. The soil is Dystric-Eutric Cambisol, mixture of sandy and clay, slightly stony and deep. The site class is medium rich to rich. In the autumn of the second and third year after the planting height, height increment and root collar diameter were measured. The survival in both experimental plantations was high but without any statistical significance of the tree shelter. The height growth of all tree species was better in tree shelter variants, with the highest average in that with Tubex Ventex Clear. The root collar diameter growth was not yet significantly affected by the use of tree shelters. As a result of research, ventilated tree shelters (Tubex Ventex Classic and Tubex Ventex Clear) may be recommended as suitable.

Funding: The work of Katharina Tabea Jungo was supported by the Swiss National Science Foundation (SNSF) (NFP 407440_167465, PI Prof. Streit) and the work of Zsofia Rozsnyai by the Swiss Society of General Internal Medicine (SGAIM) Foundation (PI Prof. Streit). The SGAIM Foundation reviewed the study protocol but did not give us feedback or help usplan, conduct, interpret results, or write this manuscript. The SNSF had the same role but did not review the study protocol. CM is funded by the National Institute for Health Research (NIHR) Applied Research Collaborations (West Midlands), the NIHR School for Primary Caren Research and an NIHR Research Professorship in General Practice (RP 2014–04-026). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. ER is supported by an NHMRC-ARC Dementia Research Development Fellowship. Background: General practitioners (GPs) should regularly review patients’ medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients’ health. However, deprescribing can be challenging for physicians. This study investigates GPs’ deprescribing decisions in 31 countries. Methods: In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs’ deprescribing decisions. Results: Of 3,175 invited GPs, 54% responded (N = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57). Interpretation: The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD. publishersversion published

Mutations in two type-3 receptor tyrosine kinases (RTKs), KIT and FLT3, are common in both acute myeloid leukaemia (AML) and systemic mastocytosis (SM) and lead to hyperactivation of key signalling pathways. A large number of tyrosine kinase inhibitors (TKIs) have been developed that target either FLT3 or KIT and significant clinical benefit has been demonstrated in multiple clinical trials. Given the structural similarity of FLT3 and KIT, it is not surprising that some of these TKIs inhibit both of these receptors. This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3-positive AML and for KIT D816V-positive SM. Here, we compare the in vitro activities of the clinically available FLT3 and KIT inhibitors with those of midostaurin against a panel of cells expressing a variety of oncogenic FLT3 or KIT receptors, including wild-type (wt) FLT3, FLT3-internal tandem duplication (ITD), FLT3 D835Y, the resistance mutant FLT3-ITD+ F691L, KIT D816V, and KIT N822K. We also examined the effects of these inhibitors in vitro and in vivo on cells expressing mutations in c-CBL found in AML that result in hypersensitization of RTKs, such as FLT3 and KIT. The results show a wide spectrum of activity of these various mutations to these clinically available TKIs.

Ellen Weisberg,1,2 Martin Sattler,1,2 Paul W Manley,3 James D Griffin1,2 1Department of Medical Oncology, Dana-Farber Cancer Institute, 2Department of Medicine, Harvard Medical School, Boston, MA, USA; 3Department of Oncology, Novartis Institutes of Biomedical Research, Basel, Switzerland Abstract: The Fms-like tyrosine kinase-3 (FLT3; fetal liver kinase-2; human stem cell tyrosine kinase-1; CD135) is a class III receptor tyrosine kinase that is normally involved in regulating the proliferation, differentiation, and survival of both hematopoietic cells and dendritic cells. Mutations leading it to be constitutively activated make it an oncogenic driver in ~30% of acute myeloid leukemia (AML) patients where it is associated with poor prognosis. The prevalence of oncogenic FLT3 and the dependency on its constitutively activated kinase activity for leukemia growth make this protein an attractive target for therapeutic intervention. Of the numerous small molecule inhibitors under clinical investigation for the treatment of oncogenic FLT3-positive AML, the N-benzoyl-staurosporine, midostaurin (CGP41251; PKC412; Rydapt®; Novartis Pharma AG, Basel, Switzerland), is the first to be approved by the US Food and Drug Administration for the treatment, in combination with standard chemotherapy, of newly diagnosed adult AML patients who harbor mutations in FLT3. Here, we describe the early design of midostaurin, the preclinical discovery of its activity against oncogenic FLT3, and its subsequent clinical development as a therapeutic agent for FLT3 mutant-positive AML. Keywords: AML, acute myeloid leukemia, PKC412, midostaurin, FLT3-ITD, oncogenic FLT3, targeted therapy

Characteristics of the eight case vignettes used in this survey. (DOCX 18 kb)

Showing MCL-1 mRNA levels do not change in Her2-positive BC cells under hypoxic conditions. Figure S2 showing a Bcl-2 is expressed in both Mcl-1wt/wt and Mcl-1Î /null MEFs. Whole-cell extracts were analyzed by immunoblotting with indicated antibodies. Immunoblotting for Erk2 confirmed equal protein loading. b EU-5346 does not change Mcl-1 mRNA expression in Her2-positive BC cells under hypoxic conditions. Figure S3 showing Mcl-1 is a potential therapeutic target not only in Her2-positive, but also in Luminal A-like and TNBC cells under hypoxic conditions. (PDF 1580 kb)

O artigo parte do reconhecimento que a formação (Bildung) encontra-se em crise, gerando transformações em todo o sistema educacional. A crise, de natureza sócio-política, projeta novas perguntas sobre as condições de possibilidade da formação e a relação homem-natureza (crise ecológica). Na análise dessa crise, assume relevância o processo de secularização, suas metamorfoses simbólicas (o deslocamento do sagrado ao profano) e as repercussões na política, em especial, para o Estado nacional. Conclui pela impossibilidade de pensar a formação sem a autocompreensão dos profundos efeitos causados pelos laços internos gerados em tal processo de secularização, que desloca elementos do sagrado ao profano, como um modo de manter vínculo social

Acute myeloid leukemia (AML) progenitors are frequently characterized by activating mutations in the receptor tyrosine kinase Fms-like tyrosine kinase-3 (FLT3). Protein tyrosine kinases are integral components of signaling cascades that have a role in both FLT3-mediated transformation as well as viability pathways that are advantageous to leukemic cell survival. The bone marrow microenvironment can diminish AML sensitivity to tyrosine kinase inhibitors. We hypothesized that inhibition of protein kinases in addition to FLT3 may be effective in overriding drug resistance in AML. We used a cell-based model mimicking stromal protection as part of an unbiased high-throughput chemical screen to identify kinase inhibitors with the potential to override microenvironment-mediated drug resistance in mutant FLT3-positive AML. Several related multi-targeted kinase inhibitors, including dasatinib, with the capability of reversing microenvironment-induced resistance to FLT3 inhibition were identified and validated. We validated synergy in vitro and demonstrated effective combination potential in vivo. In particular Janus kinase inhibitors were effective in overriding stromal protection and potentiating FLT3 inhibition in primary AML and cell lines. These results hint at a novel concept of using combination therapy to override drug resistance in mutant FLT3-positive AML in the bone marrow niche and suppress or eradicate residual disease.

The article starts from the recognition that the process of learning (Bildung) is in crisis, generating changes in the educational system. The crisis, of socio-political nature, projects new questions related to the conditions of the possibility in the learning process and the relation of man-nature (an ecological crisis). In the analysis of this crisis the process of secularization assumes an important role, its symbolic metamorphoses (the displacement of the sacred to the profane), and the impact on politics, especially in relation to the National State. It comes to the conclusion that it is impossible to think of the process of learning without self comprehension of the deep effects caused by the internal loops generated in this process of secularization, which shifts the sacred to the profane elements, as a way of maintaining social ties. O artigo parte do reconhecimento que a formação (Bildung) encontra-se em crise, gerando transformações em todo o sistema educacional. A crise, de natureza sócio-política, projeta novas perguntas sobre as condições de possibilidade da formação e a relação homem-natureza (crise ecológica). Na análise dessa crise, assume relevância o processo de secularização, suas metamorfoses simbólicas (o deslocamento do sagrado ao profano) e as repercussões na política, em especial, para o Estado nacional. Conclui pela impossibilidade de pensar a formação sem a autocompreensão dos profundos efeitos causados pelos laços internos gerados em tal processo de secularização, que desloca elementos do sagrado ao profano, como um modo de manter vínculo social.

Cancers of the head and neck and of the lung are associated with high morbidity and mortality rates that have remained relatively unchanged for more than 3 decades, despite advances in radiation therapies and chemotherapies over the same time. It is generally believed that the efficacy of standard therapy regimens has reached a plateau for these cancers. The discovery of specific aberrant molecular signaling pathways in solid tumors has afforded promising new directions for newer “targeted” cancer therapeutics. Among these, the epidermal growth factor receptor (EGFR) shows promise as a therapeutic target. Clinical studies have demonstrated that this targeted approach provides clinically meaningful benefit. This article reviews EGFR-targeted therapies in use and in development, with a focus on the role of EGFR in the pathophysiology of head and neck and lung cancer, and new concepts being investigated to improve outcomes with these agents.

MEK/ERK and NF-kB signaling pathways have been reported to play a key role in multiple myeloma (MM) survival, proliferation and drug resistance. These pathways regulate the activity of numerous transcription factors. For example, the activator protein-1 (AP-1) transcription factor has been implicated in a multitude of physiologic processes, but also tumorigenesis. However, the function of AP-1 in MM is largely unknown. Our data show a vast variety of AP-1 (c-Jun, JunB, JunD, c-Maf and c-Fos) expression levels in MM cells. Importantly, co-culture of MM cells with bone marrow stromal cells (BMSCs), i.e. isotypic primary BMSCs as well as BMSC lines KM-105 and HS-27A, rapidly and strongly induces expression of JunB, but not other AP-1 members. Previous studies have shown that JunB exerts opposite functions depending on the cellular origin and the physiopathological context. For example, it serves as a gatekeeper in acute and chronic myeloid leukemia, but as a positive regulator in Hodgkin's lymphomas and anaplastic large cell lymphomas. The relevance of JunB activity in MM growth, survival and drug resistance is elusive. First, our data demonstrate that induction of JunB is predominantly mediated by soluble factors secreted by BMSCs rather than direct MM-BMSC contact. Indeed, using cytokine arrays, we identified IL-6 among the most potent factors that trigger JunB expression. Mechanistically, JunB upregulation occurs at both transcriptional as well as translational level. Pharmacologic inhibition was used next in order to identify upstream signaling pathways, which mediate BMSC- induced JunB upregulation in MM cells. Our data show that activation of MEK/ERK or NF-kB is required for induction of JunB expression and AP-1 transcriptional activity. To delineate the specific functional role of JunB in MM pathogenesis, we transduced MM cells with pLKO.1-JunB shRNA or pLKO.1-scrambled shRNA (SCR). After puromycin- selection, effects of JunB knockdown on MM proliferation, survival and drug resistance were analyzed by 3H-thymidine incorporation, flow cytometry and western blot. Indeed, we observed significant inhibition of proliferation in MM/ JunB shRNA (decreased to ~ 25 – 40 %, p < 0.01) compared with MM/ SCR control cells, when co-cultured with BMSCs in particular. Moreover, our preliminary data show that knockdown of JunB overcomes resistance of MM cells against doxorubicin as well as melphalan. Furthermore, 4-hydroxytamoxifen (4-OHT) treatment of MM cell lines stably transduced with pMSCV-JunB-ER-IRES-GFP but not pMSCV-IRES-GFP induced significant AP-1 luciferase activity (~ 3.3 fold, p < 0.01) as well as MM cell proliferation. In ongoing experiments, the in vivo relevance of our in vitro data is evaluated in a xenograft mouse model inoculated with MM /JunB-ER-IRES-GFP and MM/ IRES-GFP cells. Finally, gene expression profiles on > 1000 MM patient samples of different prognostic groups were compared to samples from healthy donors using the gene set enrichment analysis (GSEA). Our results further support a key role for JunB in MM pathogenesis. In summary, our data demonstrate for the first time an important role of JunB/AP-1 in MM tumorigenesis and strongly propose it as a novel therapeutic target in MM. Disclosures No relevant conflicts of interest to declare.

Participating countries: number of invited GPs and response rates per country. (DOCX 21 kb)

BACKGROUND General practitioners (GPs) should regularly review patients' medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients' health. However, deprescribing can be challenging for physicians. This study investigates GPs' deprescribing decisions in 31 countries. METHODS In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs' deprescribing decisions. RESULTS Of 3,175 invited GPs, 54% responded (N = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57). INTERPRETATION The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD.

Survey. (DOCX 49 kb)

Additional file 1. Appendix 1-3.

Participating countries: number of invited GPs and response rates per country. (DOCX 21 kb)

OBJECTIVES We previously found large variations in general practitioner (GP) hypertension treatment probability in oldest-old (>80 years) between countries. We wanted to explore whether differences in country-specific cardiovascular disease (CVD) burden and life expectancy could explain the differences. DESIGN This is a survey study using case-vignettes of oldest-old patients with different comorbidities and blood pressure levels. An ecological multilevel model analysis was performed. SETTING GP respondents from European General Practice Research Network (EGPRN) countries, Brazil and New Zeeland. SUBJECTS This study included 2543 GPs from 29 countries. MAIN OUTCOME MEASURES GP treatment probability to start or not start antihypertensive treatment based on responses to case-vignettes; either low (80 years of age). • In this study including 1947 GPs from 29 countries, we found that a high country-specific cardiovascular disease (CVD) burden (i.e. myocardial infarction and/or stroke) was associated with a higher GP treatment probability in patients aged >80 years. • However, the association was modified by country-specific life expectancy at age 60. While there was a positive association for GPs in countries with a low life expectancy at age 60, there was no association in countries with a high life expectancy at age 60. • These findings help explaining some of the large variation seen in the decision as to whether or not to treat hypertension in the oldest-old.

Survey. (DOCX 49 kb)